Fig. 3.

Schematic representation of the regulatory circuit that gives rise to the bistability. α Ketoglutarate inhibits HIF1 by promoting its degradation. HIF1 inhibits the production of α ketoglutarate by inhibiting pyruvate entry into TCA. A decrease in α ketoglutarate below a threshold because of stochastic reasons would increase the HIF1 level, thus rendering a further decrease in α ketoglutarate (a). This state corresponds to state S1 in Fig. 2. Conversely, α ketoglutarate concentration above a threshold will ensure that the HIF1-mediated negative feedback loop is abolished, thus increasing the levels of α ketoglutarate (b). This state corresponds to state S2 in Fig. 2. Double-negative feedback loops of the type shown above can force the system to exist in either of the two stable states